An adhesion phenomenon is essential to a complicated life phenomenon resulted from intercellular interaction such as activation, migration, proliferation, differentiation, etc., of cells. And, cell adhesion molecules classified as integrin, immunoglobulin, selectin, cadherin, etc., are involved in the above cell-cell or cell-extracellular matrix interactions. The integrin family has an αβ-heterodimer structure and 16 different integrin α chains and 8 different integrin β chains have been identified. Integrin VLA-4 (α4β1) as one of them expresses within lymphocyte, eosinophils, basophils and monocyte, and VCAM-1 and fibronectin are ligands thereof. That is, VLA-4 plays an important role in cell-cell interactions and cell-extracellular matrix interactions mediated by VCAM-1 and fibronectin. Further, integrin LPAM-1 (α4β7) expresses within lymphocyte, eosinophils, basophils and monocyte, and VCAM-1, fibronectin and MadCAM-1 are ligands thereof. Meanwhile, for leucocytes' functioning in the inflammatory tissue, leucocytes circulating with blood are required to pass through the vascular endothelial cells and infiltrate the inflammatory site. Binding of either VLA-4 or LPAM-1 with either VCAM-1 or MadCAM-1 is one of the most important mechanisms that produce an intense adhesion between leukocytes and vascular endothelial cells. Inflammatory cells such as T lymphocyte, B lymphocyte, monocyte and eosinophils express VLA-4 and LPAM-1, and VLA-4 and LPAM-1 strongly take part in the infiltration of these cells to an inflammatory lesion. The adhesion molecules play an essential role in the activation of cells through cell-cell interactions, and it has been made clear that the VLA-4/VCAM-1 mechanism activates eosinophils to cause degranulation, and that a signal through VLA-4 takes part in the activation of antigen-specific proliferation of lymphocytes as well.
For elucidating the roles of VLA-4 and LPAM-1 in an inflammation, several studies have been made to inhibit this intermolecular binding using monoclonal antibody. For example, an anti-α4 monoclonal antibody inhibits the adhesion of VLA-4 expressing Ramos cells onto human umbilical venous endothelial cells (HUVEC) or VCAM-1-gene-transferred COS cells. The antibody has shown therapeutic and/or prophylactic effects in several animal models. For example, significant effects have been demonstrated on a rat adjuvant induced arthritis model (Barbadillo et al., Arthritis Rheumatol., 1993, 36, 95), and contact hypersensitivity and delayed-type hypersensitivity model (Ferguson and Kupper, J. Immunol., 1993, 150, 1172; Chisholm et al., Eur. J. Immunol., 1993, 23, 682). Further, the action of the antibody has been evaluated on experimental autoimmune encephalomyelitis (Yednock, Nature, 1992, 356, 63), asthma model (Abraham et al., J. Clin. Invest., 1993, 93, 776) and inflammatory bowel disease (IBD) model (Podolsky et al., J. Clin. Invest., 1993, 92, 372). Further, it has been shown that the cell adhesion with VLA-4 plays some roles in rheumatoid arthritis, nephritis, diabetes, systemic lupus erythematosus, delayed-type allergy, multiple sclerosis, arteriosclerosis, organ transparent and various malignant tumors.
Therefore, blocking of VLA-4 (α4β1) and/or LPAM-1 (α4β7) integrins with an appropriate antagonist is effective for the therapeutical treatment of the above various diseases including inflammation diseases.
Several low-molecular-weight compounds have been already proposed as VLA-4 and/or LPAM-1 antagonists. They are described in International Patent Publications Nos. WO96/22966, WO98/53817, WO01/14328, WO99/06431, WO99/06432, WO99/06436, WO99/10312, WO99/48879, WO00/18759, WO00/20396, WO99/36393, WO99/52898, WO99/62901, WO00/67746 and WO02/08206. Those compounds described in these Publications have a urea structure or phenylalanine structure and do not have any 2-phenyl-3-heteroarylpropionic acid structure of the present invention. All conventional compounds also have problems that they lack bioavailability in oral administration and are easily decomposed in vivo. There is therefore required a compound that has properties desirable for therapeutical treatment and prophylaxis and which exhibits an antagonistic function against VLA-4 and/or LPAM-1.